Amphiphilic or amphiphatic derivatives are molecules containing both polar and hydrophobic domains. One important characteristic of some amphiphilic derivatives is their ability to self organize into different structures under appropriate conditions. For example, certain amphiphilic molecules, characterized by specific polar head groups such as anionic or zwitterionic groups and one or two alkyl chains of at least 8 carbon atoms, may organize themselves into vesicles of mono- and bilayer-membranes, which encapsulate the solutions in which they are formed. Amphiphilic molecules may also aggregate and organize themselves into micelle-type structures.
Monolayer membranes can be made from amphiphiles with at least two polar heads on either side of an aliphatic chain. When such amphiphiles, having two heads of different sizes, form monolayer membranes, they are classified into two categories—unsymmetrical or symmetrical, depending on a parallel or antiparallel molecular packing within the membrane.
Bilayer vesicles can be made from: (a) amphiphiles containing two dialkyl chains such as phospholipids or nonphosphorous derivatives; (b) single chain amphiphiles comprising a polar head group, a short flexible chain, a rigid segment and a relatively long flexible chain (Kunitake et al., 1981b); and (c) triple chain amphiphiles containing two ionic head groups (Sumida et al, 2001).
Vesicles made from synthetic amphiphiles or surfactants are called synthetic or surfactant vesicles. Vesicles made from synthetic or natural phospholipids are called liposomes. Liposomes and vesicles can be mechanically stabilized by mechanisms such as polymerization to form stronger and less permeable barriers. Vesicles made from a mixture of dissimilar aliphatic chains can form membranes with a mosaic distribution of different amphiphilic derivatives to improve control of membrane permeability or achieve specific adhesion properties of the vesicle. For example, the introduction of amphiphiles with perfluoroalkyl chains into a hydrocarbon membrane will result in the formation of perfluorinated domains which can, for example, be selectively removed to form micropores in the vesicle membrane (Fuhrhop and Mathieu, 1984).
Vesicle size is an important parameter in relation to penetration through biological barriers to reach target sites. Vesicle size also influences the mechanical stability and shelf life. Vesicles made from phospholipids and other amphiphilic compounds, which form bilayer membranes, characteristically range from 200 A to 10 microns in diameter. Monolayer vesicles may be made even smaller in diameter. For many applications requiring penetration through biological barriers, vesicle sizes smaller than 1000 A would be preferred, and in many cases still more preferred are vesicles in the size range of 200 A or less. However, obtaining small size vesicles concomitant with stability is generally problematic.
Amphiphilic derivatives and micelles, complexants, surfactants and vesicles derived therefrom have applications in many fields. In medicine, for example, liposomes can be used for drug delivery (e.g. of antibiotics, chemotherapeutical agents, etc.), for diagnostics (e.g. liposomes loaded with contrast material for imaging), and for gene therapy. In agriculture amphiphilic derivatives and related products are used in various formulation for the delivery of herbicides, pesticides and micro-nutrients. In the cosmetic industry, amphiphilic derivatives and related products are used widely in formulations of lotions, creams etc.
However, the currently available amphiphilic derivatives and their related products, in particular vesicles, suffer from serious drawbacks, which limits their use for many important applications. Major problems which limit the use of vesicles, complexants and micelles are stability in relation to production, shelf life, lifetime in biological environments, accessibility to target sites, and sustained viability after administration. Notably, many applications require nanosized vesicles, which at the present time are not sufficiently stable for commercial products. Small size, concomitant with stability, is especially important in applications requiring transport via multiple biological compartments before reaching the target site.
Amphiphilic derivatives, which contain a combination of multiple interactions within the hydrophobic chains (e.g. hydrogen bonding, polar, electrostatic and hydrophobic interactions, etc.) and between moieties in close proximity to the head groups, together with inter-reactive groups (e.g. double bond, —SH, epoxy groups etc.) may overcome such limitations. Moreover, in many cases, to achieve the required performance characteristics of amphiphilic derivatives and related products (e.g. biological and mechanical stability, targeting, penetration, etc.), efficient post-formation modifications of the vesicles, micelles or complexants should be performed. State of the art methods to modify vesicle surfaces include incorporation of lipid-pendant conjugates into the membrane during vesicle preparation, or modifying the vesicle surface by reacting the pendant with reactive surface groups. An important issue of stability is to avoid lipid-pendant conjugate removal from the vesicle membrane. Currently, the poor stability of the available amphiphilic products limits the number of chemical reactions that can be used for post-formation modification, and hence, restrict the number of applications. Especially for targeting and controlled release applications, complex functional groups are needed to achieve the necessary vesicle characteristics. Such amphiphilic derivatives are either currently not available or are very expensive to produce. Achieving improved amphiphilic characteristics may be possible with derivatives that contain a combination of inter-reactive groups for stability and available reactive sites for post-formation chemical modification to achieve nanosized vesicles with targeting and controlled release features.
In order to overcome the limitation of the state of the art, amphiphilic derivatives with functional moieties on the aliphatic chain as well as in close proximity to the polar head groups can be employed. Such derivatives will allow the formation of stable vesicles, complexants and micelles, which can readily undergo subsequent modifications, prevent the removal of conjugated surface pendants, and allow better targeting and release features. Such derivatives can be synthesized from functionalized oils such as vernonia oil, castor oil, lasquerella oil and epoxidized unsaturated oils like soy and linseed oils.